Nitric oxide generating medical devices

ABSTRACT

Medical devices having a catalyst capable of catalyzing the generation of nitric oxide in vivo and methods of treating a vascular condition using the devices are provided.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/923,559, filed on 21 Jun. 2013 (published as U.S. Pat. App. Pub. No.US 2013-0287833 A1 on 31 Oct. 2013, and issuing as U.S. Pat. No.8,986,724 B2 on 24 Mar. 2015), which was a continuation of U.S. patentapplication Ser. No. 13/276,666, filed on 19 Oct. 2011 (published asU.S. Pat. App. Pub. No. 2012-0034222 A1 on 9 Feb. 2012, and issuing asU.S. Pat. No. 8,470,358 on 25 Jun. 2013), which application was adivisional application of U.S. patent application Ser. No. 11/726,135,filed on 20 Mar. 2007 (issuing as U.S. Pat. No. 8,067,025 on 29 Nov.2011), which application was a divisional application of U.S. patentapplication Ser. No. 11/356,696, filed on 17 Feb. 2006 (published asU.S. Pat. App. Pub. No. 2007-0196428 A1 on 23 Aug. 2007, and nowabandoned), all of which are incorporated by reference in their entiretyas if fully set forth herein.

FIELD

This invention is generally related to medical devices capable of invivo generation of nitric oxide.

BACKGROUND

Stents are used not only as a mechanical intervention in vascularconditions but also as a vehicle for providing biological therapy. As amechanical intervention, stents act as scaffoldings, functioning tophysically hold open and, if desired, to expand the wall of thepassageway. Typically, stents are capable of being compressed, so thatthey can be inserted through small vessels via catheters, and thenexpanded to a larger diameter once they are at the desired location.Examples in patent literature disclosing stents that have been appliedin PTCA procedures include stents illustrated in U.S. Pat. No. 4,733,665issued to Palmaz, U.S. Pat. No. 4,800,882 issued to Gianturco, and U.S.Pat. No. 4,886,062 issued to Wiktor.

Biological therapy can be achieved by medicating the stents. Medicatedstents provide for the local administration of a therapeutic substanceat the diseased site. In order to provide an efficacious concentrationto the treated site, systemic administration of such medication oftenproduces adverse or toxic side effects on the patient. Local delivery isa preferred method of treatment in that smaller total levels ofmedication are administered in comparison to systemic dosages, but areconcentrated at a specific site. Local delivery thus produces fewer sideeffects and achieves more favorable results.

In many patients, especially diabetic patients, stentable lesions arefocal manifestations of widespread vascular disease. The advent of drugdelivery stents has brought relief from restenosis of the treatedlesion, but leaves progression of regional vascular disease unaddressed.

Nitric oxide (NO) has numerous physiologic and pathophysiologicfunctions. For example, NO can inhibit the inflammatory process bylowering cytokine synthesis and inactivating nuclear factor (NF)-κB,3 asseveral cytokines contain a binding site for NF-κB in their promoterregions. It has been reported that blood level NO can inhibit plateletadhesion and aggregation, inflammation, and smooth muscle cell migrationand proliferation and can stimulate endothelial cell migration andproliferation. In addition, NO has vasorelaxant effect and can regulatesmooth muscle contractility and platelet reactivity (see, e.g.,Lindberg, L., et al., Nitric Oxide gives maximal response after coronaryartery bypass surgery. J. Cardiothorac Vasc. Anesth. 8:182-87 (1994)).

Therefore, the present invention provides means of generating nitricoxide to cure the deficiencies of a conventional drug delivery stent.

SUMMARY

A medical device is provided comprising a polymer and a metal complexattached to the polymer, wherein the metal complex catalyzes thegeneration of nitric oxide in the blood stream or in tissue adjacent tothe medical device. In some embodiments, the polymer is included in acoating for the medical device. In some embodiments, the medical deviceis a bioabsorbable stent made from at least the polymer. The metalcomplex can be a copper complex. The metal complex can comprise Cyclen,Cyclam, DTTCT, or a bipyridine ligand. The metal complex can be attachedto the polymer with a spacer. The spacer can be a short-chain alkylgroup, phenyl group, an aryl group, or poly(ethylene glycol). In someembodiments, the metal complex comprises a metal selected from the groupconsisting of Cu²⁺, Co²⁺, Ni²⁺, Zn⁺²⁺, Mn²⁺, Al³⁺, or Fe³⁺. The medicaldevice can include a drug adapted to be released from the device. Thedrug can be included in a coating. The coating can be made from thepolymer to which the complex is attached. The nitric oxide can bereleased from a nitrosylated biomolecule present in the blood stream ora tissue adjacent to the medical device. The nitric oxide can bereleased from a nitrosylated protein or S-nitrosothiols present in theblood stream or in tissue adjacent to the medical device.

In accordance with another aspect of the invention, a medical devicecomprising a metal complex is provided, wherein the metal complex isattached to the surface of the medical device or a coating on themedical device, and wherein the metal complex catalyzes the generationof nitric oxide in the blood stream or in tissue adjacent to the medicaldevice.

DETAILED DESCRIPTION

The present invention provides methods for generating NO in blood.According to embodiments of the present invention, NO can be releasedfrom a nitric oxide source present in the blood stream or a tissue whenthe nitric oxide source meets a metal catalyst in the blood stream orthe tissue. The metal catalyst can be attached to a coating (e.g., atopcoat) on a medical device with a spacer. Upon exposure to the bloodstream or the tissue, the metal catalyzes the release of NO from the NOsource. The nitric oxide source can comprise nitrosylated biomoleculessuch as nitrosylated proteins (e.g., S-nitrosothiols).

NO has numerous physiologic and pathophysiologic functions. For example,NO can inhibit the inflammatory process by lowering cytokine synthesisand inactivating nuclear factor (NF)-κB,3 as several cytokines contain abinding site for NF-κB in their promoter regions. It has been reportedthat blood level NO can inhibit platelet adhesion and aggregation,inflammation, and smooth muscle cell migration and proliferation and canstimulate endothelial cell migration and proliferation. In addition, NOhas vasorelaxant effect and can regulate smooth muscle contractility,and platelet reactivity.

The metal catalyst includes a metal, which can be a metal ion or a metalatom, and one or more ligands. The ligand can have two or morecoordination sites. Preferably, the ligand has four nitrogen atoms thatserve as coordination sites in the ligand. The metal catalyst can beformed prior to the ligand's attachment to a polymer coating or afterthe ligand's attachment to the polymer coating. Preferably, the catalystis formed after the ligand's attachment to the coating.

In some embodiments, a coating including the metal complex describedherein can be formed directly on the surface of a medical device or ontop of a layer of a coating that includes a biocompatible polymer. Insome embodiments, the coating can be formed on top of a drug reservoir,which can be a layer of neat or pure drug(s) or a layer that includes abiocompatible polymer combined with a drug or combination of drugs.

In some embodiments, the medical device itself can be bioabsorbable(e.g., a bioabsorbable stent) and the catalyst can be attached directlyto the surface of the device. In some embodiments, the catalyst can alsobe attached to a coating of the bioabsorbable device.

The medical device having the catalyst described herein can include oneor more biocompatible polymer(s) and optionally one or morebiobeneficial material(s). In some embodiments, the coating can includea bioactive agent such as a drug. Some examples of the bioactive agentsinclude, but are not limited to, paclitaxel, docetaxel, estradiol,nitric oxide donors, super oxide dismutases, super oxide dismutasesmimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N-1-tetrazolyl)-rapamycin (ABT-578), pimecrolimus, imatinibmesylate, midostaurin, clobetasol, bioactive RGD, CD-34 antibody,abciximab (REOPRO), progenitor cell capturing antibody, prohealingdrugs, prodrugs thereof, co-drugs thereof, or a combination thereof.

The medical device including a catalyst described herein can be used totreat, prevent, or ameliorate a vascular medical condition such asatherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissectionor perforation, vascular aneurysm, vulnerable plaque, chronic totalocclusion, claudication, anastomotic proliferation for vein andartificial grafts, bile duct obstruction, ureter obstruction, tumorobstruction, or combinations thereof.

Metal Complexes

Copper complexes have been shown to generate biologically relevantlevels of NO for up to 6 hours (see, e.g., Oh, B. K. and Meyerhoff, M.E., Biomaterials 25:283-293 (2005)). NO generation occurs as long as thecopper catalyst is present and a nitrosylated biomolecule (e.g.,nitrosylated proteins or S-nitrosothiols) in the blood reaches thecopper catalyst (see, e.g., Oh, B. H., Meyerhoff, M. E., J. Amer. Chem.Soc., 125(32):9552-53) (2003). NO generation can be achieved when ametal ion (e.g., copper or zinc) is bound to a ligand such as Cyclen(see Scheme I), Cyclan (see Scheme I), or macrocycles having fournitrogen groupings. One such macrocycle ligand isdibenzo[e,k]-2,3,8,9-tetraphenyl-1,4,7,10-tetraaza-cyclododeca-1,3,7,9-tetraene(DTTCT). The electronic and steric environment provided by the ligandsinfluences the metal ion's reactivity and selectivity. Therefore, it isimportant not to significantly modify the structure of the macrocycle inattaching the ligand to a polymer in the coating on a medical device.

The metal catalyst can be any metal complex capable of catalyzing thegeneration of nitric oxide in the blood stream or the tissue. In someembodiments, the metal complex is a copper complex. In some embodiments,the metal complex contains a metal such as Co²⁺, Ni²⁺, Zn⁺²⁺, Mn²⁺,Al³⁺, or Fe³⁺.

The metal complex can be formed by mixing a metal compound and theligand described herein and allowing the ligand to complex with themetal. Methods for forming a metal complex are well documented in theart. Some references can be found in A.B.P. Lever, Editor-in-Chief,Coordination Chemistry Reviews, published by Elsevier.

Ligands useful for forming the metal complex described herein arechelating ligands having multiple coordination sites. The ligands canhave at least two coordination sites, preferably three coordinationsites, more preferably four coordination sites. In some embodiments, theligand is an N4 macrocycle ligand (a ligand having four nitrogencoordination sites). Some representative N4 ligands include, but are notlimited to, Cyclen, Cyclam, and DTTCT.

In some embodiments, the ligand can have two coordination sites. Two ormore equivalents of the ligands can complex to a metal to form a metalcomplex. For example, two equivalents of an N2 ligand (ligand having twonitrogen coordination sites) can complex to a metal such as copper toform a metal complex having four nitrogen coordination sites. Somerepresentative N2 ligands are, for example, 2,2′-bipyridine ligands.

Standard procedures can be used to introduce the metal (e.g., a metalion) into the macrocycle.

To have a local generation of NO, in some embodiments, the metal complexdescribed herein is attached to the surface of a medical device or acoating on the device through a spacer. The spacer can be, for example,an alkyl chain or a poly(ethylene glycol) (PEG) chain. The spacer has alength of at least two carbon atoms or longer. This can allow the coppercomplex to be at the blood polymer interface and have the active centeraccessible to nitrosylated biomolecules (e.g., nitrosylated proteins ornitrosothiols) in the blood. The metal complex can either be coupled tothe spacer and then to the polymer or coupled to a spacer that isalready attached to the polymer. The order of the reactions is dictatedby the compatibility of the chemistry, which can be readily appreciatedby one of ordinary skill in the art.

Exemplary spacers that can be used in the present invention include, butare not limited to, PEG, poly(alkylene oxide) such as poly(ethyleneoxide) (PEO) and poly(propylene oxide) (PPO), C2-C20 alkyls, and shortpeptides. In some embodiments, the spacer can be a biocompatible polymeror oligomer.

Synthesis and/or Functionalization of Ligands

Attachment of a spacer to ligands can be achieved by functionalizing theligand and then coupling the functionalized ligand to a spacer.Functionalization of the ligand can be carried out using standardprocedures in organic synthesis. To illustrate, Cyclen and Cyclam, bothhaving N—H groups in their molecules, can be coupled to a spacer thathas a leaving group such as a halo group and a reactive group R, whichcan be any reactive group such as carboxyl, hydroxyl, thiol, or aminegroups (Scheme I). The reactive group can be used to attach Cyclen orCyclam to the reactive groups available on the polymer.

In some embodiments, the free reactive groups on a ligand (such as N—Hgroups on Cyclam) can be selectively protected by a protective groupsuch as t-bock. The remaining reactive group can then be used to attachthe ligand to a spacer. Other N4 macrocycles, such as DTTCT, can besynthesized to bear functional groups by selecting functionalizedstarting materials. As shown in Scheme II, two molecules of a diaminewith an R1 group, which can have a protected functional group such ashydroxyl, amine or carboxylic acid group, can react with two moleculesof a diketone having R2 groups to form a N4 macrocycle (Scheme II).

In Scheme II, where the diamine is 1,2-di-amine-benzene and the R2 groupof the diketone is a phenyl group, the N4 macrocycle is DTTCT, which canform a copper complex as shown below:

Other methods for functionalizing macrocyclic ligands are welldocumented. For example, acylations of phenyls can be done by aFriedel-Crafts reaction (Bryce-Smith D. J.; J. Chem. Soc., 1963, 5983,and Benkeser et al. J. Am. Chem. Soc. 1963, 85, 3984). Acyl halides(Bryce-Smith D. J. et al., J. Chem. Soc. 1954, 2743 and Pocker Y. et al.J. Am. Chem. Soc. 1968, 90, 6764) are the most common reagents, butcarboxylic acids, anhydrides and ketenes can also be used. For examplean acid chloride (RCOCl) can attack the hydrogen on the phenyl (R2 inScheme II=phenyl) to yield ROCR2. Alternatively, a Suzuki coupling(Miyaura N. and Suzuki A., Chem. Rev. 1995, 95, 2457) can be performedbetween an organo-boronic acid and halides using a palladium catalyst.It is noteworthy that the Suzuki coupling is a milder reaction. In someembodiments, reactive groups on the ligand or the polymer may need to beprotected (t-BOC, etc.) to avoid undesirable side reactions. In someembodiments, to obtain a single attachment point, less than 1 equivalentof acid chloride can be added. Subsequent purification can be needed.

Coupling of Spacer to Polymer

Coupling of spacers to a polymer in a coating or on the surface of amedical device can be achieved using two mechanisms. In someembodiments, the metal complex can be coupled to a polymer and thensprayed as a coating onto the medical device. In some embodiments, thepolymer can be applied to the medical device and the metal complex canbe subsequently coupled to the polymer coating. This approach cangenerate a coating having a higher surface density of the metal complex.The polymer should have reactive side groups such as hydroxyls,carboxylic acids, amines, etc. In some embodiments the medical device,such as a bioabsorbable polymer stent, can be made to include the metalcomplex.

In some embodiments, the polymer (e.g., coating or the device surface)has mildly reactive hydroxyl groups. The spacer should have reactivegroups such as a carboxylic acid, N-hydroxysuccinimide (NHS), an acidhalide (e.g., acid chloride) or equivalent thereof, or a vinyl sulphone.A carboxylic acid or NHS can be readily coupled to a hydroxyl group inthe presence of N,N′-carbonyldiimidazole or dicyclohexylcarbodiimide(DCC), which are commercially available.

In some embodiments, the spacer can be poly(ethylene glycol) (PEG). PEGcan be readily functionalized using acryloyl chloride to bear anacryloyl chloride end group. This end group can serve to couple PEG tothe reactive groups on the polymer.

In some embodiments, the spacer can comprise vinyl sulphone, which canbe readily coupled to the polymer under acidic conditions. Vinylsulphone is commercially available.

As an example, Scheme III shows coupling of a copper complex to ahydroxyl functional methacrylate via a PEG spacer.

Biocompatible Polymers

A biocompatible polymer can be applied to a device and then coupled tothe metal complex so as to form a coating. In some embodiments, thebiocompatible polymer can be coupled with the metal complex, andafterwards be sprayed onto a device as a coating.

The biocompatible polymer can be biodegradable (either bioerodable orbioabsorbable or both) or nondegradable and can be hydrophilic orhydrophobic. Representative biocompatible polymers include, but are notlimited to, poly(ester amide), polyhydroxyalkanoates (PHA),poly(3-hydroxyalkanoates) such as poly(3-hydroxypropanoate),poly(3-hydroxybutyrate), poly(3-hydroxyvalerate),poly(3-hydroxyhexanoate), poly(3-hydroxyheptanoate) andpoly(3-hydroxyoctanoate), poly(4-hydroxyalkanaote) such aspoly(4-hydroxybutyrate), poly(4-hydroxyvalerate),poly(4-hydroxyhexanote), poly(4-hydroxyheptanoate),poly(4-hydroxyoctanoate) and copolymers including any of the3-hydroxyalkanoate or 4-hydroxyalkanoate monomers described herein orblends thereof, poly(D,L-lactide), poly(L-lactide), polyglycolide,poly(D,L-lactide-co-glycolide), poly(L-lactide-co-glycolide),polycaprolactone, poly(lactide-co-caprolactone),poly(glycolide-co-caprolactone), poly(dioxanone), poly(ortho esters),poly(anhydrides), poly(tyrosine carbonates) and derivatives thereof,poly(tyrosine ester) and derivatives thereof, poly(imino carbonates),poly(glycolic acid-co-trimethylene carbonate), polyphosphoester,polyphosphoester urethane, poly(amino acids), polycyanoacrylates,poly(trimethylene carbonate), poly(iminocarbonate), polyphosphazenes,silicones, polyesters, polyolefins, polyisobutylene andethylene-alphaolefin copolymers, acrylic polymers and copolymers, vinylhalide polymers and copolymers, such as polyvinyl chloride, polyvinylethers, such as polyvinyl methyl ether, polyvinylidene halides, such aspolyvinylidene chloride, polyacrylonitrile, polyvinyl ketones, polyvinylaromatics, such as polystyrene, polyvinyl esters, such as polyvinylacetate, copolymers of vinyl monomers with each other and olefins, suchas ethylene-methyl methacrylate copolymers, acrylonitrile-styrenecopolymers, ABS resins, and ethylene-vinyl acetate copolymers,polyamides, such as Nylon 66 and polycaprolactam, alkyd resins,polycarbonates, polyoxymethylenes, polyimides, polyethers, poly(glycerylsebacate), poly(propylene fumarate), poly(n-butyl methacrylate),poly(sec-butyl methacrylate), poly(isobutyl methacrylate),poly(tert-butyl methacrylate), poly(n-propyl methacrylate),poly(isopropyl methacrylate), poly(ethyl methacrylate), poly(methylmethacrylate), epoxy resins, polyurethanes, rayon, rayon-triacetate,cellulose acetate, cellulose butyrate, cellulose acetate butyrate,cellophane, cellulose nitrate, cellulose propionate, cellulose ethers,carboxymethyl cellulose, polyethers such as poly(ethylene glycol) (PEG),copoly(ether-esters) (e.g. poly(ethylene oxide-co-lactic acid)(PEO/PLA)), polyalkylene oxides such as poly(ethylene oxide),poly(propylene oxide), poly(ether ester), polyalkylene oxalates,phosphoryl choline, choline, poly(aspirin), polymers and co-polymers ofhydroxyl bearing monomers such as 2-hydroxyethyl methacrylate (HEMA),hydroxypropyl methacrylate (HPMA), hydroxypropylmethacrylamide, PEGacrylate (PEGA), PEG methacrylate,2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinyl pyrrolidone(VP), carboxylic acid bearing monomers such as methacrylic acid (MA),acrylic acid (AA), alkoxymethacrylate, alkoxyacrylate, and3-trimethylsilylpropyl methacrylate (TMSPMA),poly(styrene-isoprene-styrene)-PEG (SIS-PEG), polystyrene-PEG,polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG,poly(methyl methacrylate)-PEG (PMMA-PEG), polydimethylsiloxane-co-PEG(PDMS-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), PLURONIC™surfactants (polypropylene oxide-co-polyethylene glycol),poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone),biomolecules such as collagen, chitosan, alginate, fibrin, fibrinogen,cellulose, starch, dextran, dextrin, hyaluronic acid, fragments andderivatives of hyaluronic acid, heparin, fragments and derivatives ofheparin, glycosamino glycan (GAG), GAG derivatives, polysaccharide,elastin, or combinations thereof. In some embodiments, the topcoat canexclude any one of the aforementioned polymers.

As used herein, the terms poly(D,L-lactide), poly(L-lactide),poly(D,L-lactide-co-glycolide), and poly(L-lactide-co-glycolide) can beused interchangeably with the terms poly(D,L-lactic acid), poly(L-lacticacid), poly(D,L-lactic acid-co-glycolic acid), or poly(L-lacticacid-co-glycolic acid), respectively.

Bioactive Agents

The medical device having the metal complex described herein can includeone or more bioactive agent(s), which can be therapeutic, prophylactic,or diagnostic agent(s). These agents can have anti-proliferative oranti-inflammatory properties or can have other properties such asantineoplastic, antiplatelet, anti-coagulant, anti-fibrin,antithrombogenic, antimitotic, antibiotic, antiallergic, andantioxidant. The agents can be cystostatic agents, agents that promotethe healing of the endothelium such as NO releasing or generatingagents, agents that attract endothelial progenitor cells, agents thatpromote the attachment, migration and proliferation of endothelial cells(e.g., natriuretic peptides such as CNP, ANP or BNP peptide or an RGD orcRGD peptide), while impeding smooth muscle cell proliferation. Examplesof suitable therapeutic and prophylactic agents include syntheticinorganic and organic compounds, proteins and peptides, polysaccharidesand other sugars, lipids, and DNA and RNA nucleic acid sequences havingtherapeutic, prophylactic or diagnostic activities. Some other examplesof the bioactive agent include antibodies, receptor ligands, enzymes,adhesion peptides, blood clotting factors, inhibitors or clot dissolvingagents such as streptokinase and tissue plasminogen activator, antigensfor immunization, hormones and growth factors, oligonucleotides such asantisense oligonucleotides and ribozymes and retroviral vectors for usein gene therapy. Examples of anti-proliferative agents include rapamycinand its functional or structural derivatives,40-O-(2-hydroxy)ethyl-rapamycin (everolimus), and its functional orstructural derivatives, paclitaxel and its functional and structuralderivatives. Examples of rapamycin derivatives include40-epi-(N1-tetrazolyl)-rapamycin (ABT-578),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.Examples of paclitaxel derivatives include docetaxel. Examples ofantineoplastics and/or antimitotics include methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples ofsuch antiplatelets, anticoagulants, antifibrin, and antithrombinsinclude sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, thrombin inhibitorssuch as Angiomax (Biogen, Inc., Cambridge, Mass.), calcium channelblockers (such as nifedipine), colchicine, fibroblast growth factor(FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists,lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol loweringdrug, brand name Mevacor® from Merck & Co., Inc., Whitehouse Station,N.J.), monoclonal antibodies (such as those specific forPlatelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), nitric oxide or nitric oxidedonors, super oxide dismutases, super oxide dismutase mimetic,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), estradiol,anticancer agents, dietary supplements such as various vitamins, and acombination thereof. Examples of anti-inflammatory agents includingsteroidal and non-steroidal anti-inflammatory agents include tacrolimus,dexamethasone, clobetasol, or combinations thereof. Examples ofcytostatic substances include angiopeptin, angiotensin converting enzymeinhibitors such as captopril (e.g. Capoten® and Capozide® fromBristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril(e.g. Prinivil® and Prinzide® from Merck & Co., Inc., WhitehouseStation, N.J.). An example of an antiallergic agent is permirolastpotassium. Other therapeutic substances or agents which may beappropriate include alpha-interferon, pimecrolimus, imatinib mesylate,midostaurin, bioactive RGD, SIKVAV peptides, elevating agents such ascANP or cGMP peptides, and genetically engineered endothelial cells. Theforegoing substances can also be used in the form of prodrugs orco-drugs thereof. The foregoing substances also include metabolitesthereof and/or prodrugs of the metabolites. The foregoing substances arelisted by way of example and are not meant to be limiting. Other activeagents which are currently available or that may be developed in thefuture are equally applicable.

The dosage or concentration of the bioactive agent required to produce afavorable therapeutic effect should be less than the level at which thebioactive agent produces toxic effects and greater than non-therapeuticlevels. The dosage or concentration of the bioactive agent can dependupon factors such as the particular circumstances of the patient, thenature of the trauma, the nature of the therapy desired, the time overwhich the administered ingredient resides at the vascular site, and ifother active agents are employed, the nature and type of the substanceor combination of substances. Therapeutically effective dosages can bedetermined empirically, for example by infusing vessels from suitableanimal model systems and using immunohistochemical, fluorescent orelectron microscopy methods to detect the agent and its effects, or byconducting suitable in vitro studies. Standard pharmacological testprocedures to determine dosages are understood by one of ordinary skillin the art.

Examples of Medical Device

As used herein, a medical device may be any suitable medical substratethat can be implanted in a human or veterinary patient. Examples of suchmedical devices include self-expandable stents, balloon-expandablestents, stent-grafts, grafts (e.g., aortic grafts), heart valveprostheses, cerebrospinal fluid shunts, electrodes, pacemakerelectrodes, catheters, sensors, endocardial leads (e.g., FINELINE® andENDOTAK®, available from Guidant Corporation, Santa Clara, Calif.),anastomotic devices and connectors, orthopedic implants such as screws,spinal implants, and electro-stimulatory devices. The underlyingstructure of the device can be of virtually any design. The device canbe made of a metallic material or an alloy such as, but not limited to,cobalt chromium alloy (ELGILOY®), stainless steel (316L), high nitrogenstainless steel, e.g., BIODUR® 108, cobalt chrome alloy L-605, “MP35N,”“MP20N,” ELASTINITE® (Nitinol), tantalum, nickel-titanium alloy,platinum-iridium alloy, gold, magnesium, or combinations thereof.“MP35N” and “MP20N” are trade names for alloys of cobalt, nickel,chromium and molybdenum available from Standard Press Steel Co.,Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20%chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum. Devices made frombioabsorbable or biostable polymers could also be used with theembodiments of the present invention. In some embodiments, the device isa bioabsorbable stent, with or without a coating, such that the complexis attached to the coating or the surface of the device itself.

Method of Use

In accordance with embodiments of the invention, a medical device havingthe metal complex described herein can be used for the generation ofnitric oxide in the blood stream or tissue adjacent to the medicaldevice.

Preferably, the medical device is a stent. The stent described herein isuseful for a variety of medical procedures, including, by way ofexample, treatment of obstructions caused by tumors in bile ducts,esophagus, trachea/bronchi and other biological passageways. A stenthaving the above-described coating is particularly useful for treatingdiseased regions of blood vessels caused by lipid deposition, monocyteor macrophage infiltration, or dysfunctional endothelium or acombination thereof, or occluded regions of blood vessels caused byabnormal or inappropriate migration and proliferation of smooth musclecells, thrombosis, and restenosis. Stents may be placed in a wide arrayof blood vessels, both arteries and veins. In some embodiments, thedevice described herein can be in dialysis, as grafts, or fistulae.

Representative examples of sites include the iliac, renal, carotid andcoronary arteries.

For implantation of a stent, an angiogram is first performed todetermine the appropriate positioning for stent therapy. An angiogram istypically accomplished by injecting a radiopaque contrasting agentthrough a catheter inserted into an artery or vein as an x-ray is taken.A guidewire is then advanced through the lesion or proposed site oftreatment. Over the guidewire is passed a delivery catheter which allowsa stent in its collapsed configuration to be inserted into thepassageway. The delivery catheter is inserted either percutaneously orby surgery into the femoral artery, brachial artery, femoral vein, orbrachial vein, and advanced into the appropriate blood vessel bysteering the catheter through the vascular system under fluoroscopicguidance. A stent having the above-described features may then beexpanded at the desired area of treatment. A post-insertion angiogrammay also be utilized to confirm appropriate positioning.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

What is claimed:
 1. A medical device comprising a metal complexcomprising a metal and at least one ligand, at least one of the ligandsbeing a bipyridine ligand; wherein the metal complex attaches to asurface of the medical device or a coating on the medical device, andwherein the metal complex catalyzes the in-vivo generation of nitricoxide.
 2. The medical device of claim 1, wherein the in vivo generationof nitric oxide is nitric oxide generation in a blood stream or a tissueadjacent to the medical device.
 3. The medical device of claim 1,wherein the coating on the medical device is present; and wherein thecoating comprises a polymer to which the metal complex is attached. 4.The medical device of claim 1, wherein the medical device is abioabsorbable stent comprising a polymer to which the metal complex is aattached.
 5. The medical device of claim 1, wherein the metal of themetal complex comprises copper.
 6. The medical device of claim 1,wherein the metal complex attaches to a surface of the medical device.7. The medical device of claim 1, wherein the metal of the metal complexcomprises a member of the group consisting of Cu, Co, Ni, Zn, Mn, Al,and Fe.
 8. The medical device of claim 1, wherein the metal complexcomprises an ion selected from the group consisting of Cu²⁺, Co²⁺, Ni²⁺,Zn²⁺, Mn²⁺, Al³⁺, and Fe³⁺.
 9. The medical device of claim 1, furthercomprising a drug.
 10. The medical device of claim 9, wherein the drugis selected from the group consisting of paclitaxel, docetaxel,estradiol, super oxide dismutases, tacrolimus, dexamethasone, rapamycin,everolimus, 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), pimecrolimus, imatinibmesylate, midostaurin, clobetasol, bioactive RGD, CD-34 antibody,abciximab (REOPRO), and combinations thereof.
 11. The medical device ofclaim 9, wherein the coating on the medical device is present and thecoating comprises the drug.
 12. The medical device of claim 11, whereinthe coating comprises a polymer to which the metal complex is attached.13. The medical device of claim 11, wherein the drug is selected fromthe group consisting of paclitaxel, docetaxel, estradiol, super oxidedismutases, tacrolimus, dexamethasone, rapamycin, everolimus,40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), pimecrolimus, imatinibmesylate, midostaurin, clobetasol, bioactive RGD, CD-34 antibody,abciximab (REOPRO), and combinations thereof.
 14. The medical device ofclaim 1, which is a stent.
 15. The medical device of claim 1, which is abioabsorbable stent.
 16. The medical device of claim 1, wherein thenitric oxide is released from a nitrosylated biomolecule present in ablood stream or a tissue adjacent to the medical device.
 17. The medicaldevice of claim 1, wherein the nitric oxide is released from anitrosylated protein or an S-nitrosothiol present in a blood stream or atissue adjacent to the medical device.
 18. A method of treating adisorder in a patient comprising implanting in the patient the medicaldevice of claim 1, wherein the disorder is selected from the groupconsisting of atherosclerosis, thrombosis, restenosis, hemorrhage,vascular dissection or perforation, vascular aneurysm, vulnerableplaque, chronic total occlusion, claudication, anastomotic proliferationfor vein and artificial grafts, bile duct obstruction, ureterobstruction, tumor obstruction, diabetic vascular disease, andcombinations thereof.
 19. A method of treating a disorder in a patientcomprising implanting in the patient the medical device of claim 10,wherein the disorder is selected from the group consisting ofatherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissectionor perforation, vascular aneurysm, vulnerable plaque, chronic totalocclusion, claudication, anastomotic proliferation for vein andartificial grafts, bile duct obstruction, ureter obstruction, tumorobstruction, diabetic vascular disease, and combinations thereof.
 20. Amethod of treating a disorder in a patient comprising implanting in thepatient the medical device of claim 13, wherein the disorder is selectedfrom the group consisting of atherosclerosis, thrombosis, restenosis,hemorrhage, vascular dissection or perforation, vascular aneurysm,vulnerable plaque, chronic total occlusion, claudication, anastomoticproliferation for vein and artificial grafts, bile duct obstruction,ureter obstruction, tumor obstruction, diabetic vascular disease, andcombinations thereof.